Insomnia with objective short sleep duration in women with temporomandibular joint disorder: quantitative sensory testing, inflammation and clinical pain profiles.
Temporomandibular joint disorder (TMD) is a disabling facial pain syndrome with a high prevalence of insomnia that primarily affects women. Insomnia with objective short sleep duration (ISSD) is an emerging phenotype linked to cardiometabolic morbidity and increased mortality. The present report examines the association of ISSD on clinical and laboratory pain and systemic inflammation in TMD. We collected baseline data from 128 women with TMD and insomnia as part of a clinical trial evaluating psychological interventions for sleep and pain. Participants completed self-report questionnaires, one-night polysomnography, a two-week actigraphy assessment, quantitative sensory testing (QST) to assess cold pain tolerance, pain sensitivity and central sensitization and circulating Interleukin-6 levels were measured to assess systemic inflammation. 24.2% (n = 31) of the sample met criteria for ISSD [polysomnography (sleep duration <6 h)]. Compared to those with insomnia and normal sleep duration, ISSD were older (40.4 vs. 34.9,p < 0.05) and a greater proportion self-identified as Black (48.4% vs 11.3%,p < 0.001). Multivariate regressions revealed that ISSD endorsed higher self-report pain severity and functional limitation of the jaw. ISSD also demonstrated increased generalized pain sensitivity, enhanced central sensitization, cold pressor tolerance and higher resting interleukin-6 levels. This is the first study to characterize the ISSD phenotype in a chronic pain sample and expand the scope of its negative health outcomes to chronic pain. ISSD may be an important chronic pain phenotype associated with a more severe clinical and laboratory pain profile, and future studies should focus on implications for treatment response and disease trajectory. ClinicalTrials.gov Identifier: NCT01794624.


RAF-Mutant Melanomas Differentially Depend on ERK2 Over ERK1 to Support Aberrant MAPK Pathway Activation and Cell Proliferation.
Half of advanced human melanomas are driven by mutant BRAF and dependent on MAPK signaling. Interestingly, the results of three independent genetic screens highlight a dependency of BRAF-mutant melanoma cell lines on BRAF and ERK2, but not ERK1. ERK2 is expressed higher in melanoma compared with other cancer types and higher than ERK1 within melanoma. However, ERK1 and ERK2 are similarly required in primary human melanocytes transformed with mutant BRAF and are expressed at a similar, lower amount compared with established cancer cell lines. ERK1 can compensate for ERK2 loss as seen by expression of ERK1 rescuing the proliferation arrest mediated by ERK2 loss (both by shRNA or inhibition by an ERK inhibitor). ERK2 knockdown, as opposed to ERK1 knockdown, led to more robust suppression of MAPK signaling as seen by RNA-sequencing, qRT-PCR, and Western blot analysis. In addition, treatment with MAPK pathway inhibitors led to gene expression changes that closely resembled those seen upon knockdown of ERK2 but not ERK1. Together, these data demonstrate that ERK2 drives BRAF-mutant melanoma gene expression and proliferation as a function of its higher expression compared with ERK1. Selective inhibition of ERK2 for the treatment of melanomas may spare the toxicity associated with pan-ERK inhibition in normal tissues. IMPLICATIONS: BRAF-mutant melanomas overexpress and depend on ERK2 but not ERK1, suggesting that ERK2-selective inhibition may be toxicity sparing.


Sex differences in contractile properties and fatigue resistance of human skeletal muscle.
To explore the cause of higher skeletal muscle fatigue resistance in women than men, we used electrically evoked contractions (1 s on, 1 s off, 30 Hz, 2 min), which circumvent motivational bias and allow examination of contractile properties. We compared 29 men [26.5 (7.0) years old; mean (s.d.)] with 35 women [25.4 (7.6) years old]. Strength of the quadriceps muscle was higher in men than women (P < 0.001). The lower maximal rate of relaxation in women (P = 0.002) indicates that their muscles were slower than those of men. The torque declined less in women than in men [37.7 (10.7) versus 29.9 (10.0)%; P = 0.002], and was not related to muscle strength or size, as determined with magnetic resonance imaging. The sex difference in fatigability was also seen when the circulation to the leg was occluded [torque declined 76.9 (10.8) versus 59.5 (16.9)% in men versus women, respectively; P = 0.008]. The maximal rate of relaxation correlated with the fatigability of the muscle under all conditions (correlations ranging from 0.34 to 0.51, P < 0.02). We conclude that the sex-related difference in skeletal muscle fatigue resistance is not explicable by differences in motivation, muscle size, oxidative capacity and/or blood flow between sexes, but might be related to differences in fibre type composition.


Phylodynamic theory of persistence, extinction and speciation of rapidly adapting pathogens.
Rapidly evolving pathogens like influenza viruses can persist by changing their antigenic properties fast enough to evade the adaptive immunity, yet they rarely split into diverging lineages. By mapping the multi-strain Susceptible-Infected-Recovered model onto the traveling wave model of adapting populations, we demonstrate that persistence of a rapidly evolving, Red-Queen-like state of the pathogen population requires long-ranged cross-immunity and sufficiently large population sizes. This state is unstable and the population goes extinct or 'speciates' into two pathogen strains with antigenic divergence beyond the range of cross-inhibition. However, in a certain range of evolutionary parameters, a single cross-inhibiting population can exist for times long compared to the time to the most recent common ancestor ([Formula: see text]) and gives rise to phylogenetic patterns typical of influenza virus. We demonstrate that the rate of speciation is related to fluctuations of [Formula: see text] and construct a 'phase diagram' identifying different phylodynamic regimes as a function of evolutionary parameters.


Health and Safety in the Legal Cannabis Industry Before and During COVID-19.
In 2020, medical cannabis is legal in thirty-six states and adult use ("recreational") cannabis is legal in fifteen, despite cannabis remaining illegal at the federal level. Up to 250,000 individuals work as full-time employees in cannabis. During the COVID-19 pandemic, California, Colorado, and other states deemed medical cannabis business as essential, raising occupational challenges and safety issues for cannabis employees. In 2020, interviews were conducted with Ethan, an extraction lab assistant in Las Vegas; Haylee, a trainer with a cannabis company in Sacramento; and Belinda, a Wisconsin-based occupational health and safety trainer, to showcase concerns and experiences in cannabis workplaces and training programs. Findings from interviews reveal pro-worker activities to promote workplace safety and labor unionism while large multistate operators seek to optimize profits and obstruct workers' rights. Knowledge gained through the interviews contributes to discussions to lessen the potential exposure of the cannabis workforce to COVID 19.


Predicting the Risk of Intimate Partner Violence: The Chinese Risk Assessment Tool for Victims.
The present study reports the development and validation of the Chinese Risk Assessment Tool for Victims (CRAT-V), an actuarial instrument for the prediction of intimate partner violence (IPV) victimization in a Chinese population. Data were collected from a representative sample of 2,708 Chinese women who were married or cohabiting in Hong Kong. All participants were interviewed with a questionnaire assessing their experience of IPV victimization and personal or family factors related to IPV. As measured by the Revised Conflict Tactics Scale (CTS 2), the base rates of preceding-year physical and sexual IPV victimization were 4.6 % and 3.6 %, respectively. Using a cross-validation procedure, the present study developed a 5-factor instrument with one half of the randomly split sample and validated the resulting tool with the other half. The CRAT-V had a sensitivity of 74.0 %, a specificity of 68.3 %, an overall accuracy of 68.7 %, and an area under the receiver operating characteristic (ROC) curve of 0.75 when administered on the second half of sample. Overall, the CRAT-V may serve as a straightforward, systematic, and easy-to-administer instrument tailor-made for Chinese populations for the assessment of risk of IPV victimization against women.


Discharge planning effect on length of hospital stay.
The impact of discharge planning was measured in 3 community hospitals by comparing the annual median length of stay by diagnosis for 2 years before and for 2 years after the introduction of discharge planning. Congestive heart failure, cerebrovascular accident, chronic obstructive pulmonary disease and fractured hip were the diagnoses studied. Either cataract or benign prostatic hypertrophy served as the control diagnosis. Criteria were established to identify changes in length of stay which could be attributed to discharge planning. The results indicated that with the onset of discharge planning, the length of stay increased for some diagnoses and decreased for others at each hospital. The effect among the hospitals also appears to have been inconsistent.


Antihypertensive Effect of Polyphenol-Rich Fraction of Azadirachta indica on Nω-Nitro-L-Arginine Methyl Ester-Induced Hypertension and Cardiorenal Dysfunction.
Azadirachta indica (AI) is a medicinal plant with reported antioxidant and cardio-protective properties. The use of plant-based polyphenols has become greatly increased in the last one decade. The present study investigated the protective effect of the polyphenol-rich fraction (PRF) of the methanol-extract of Azadirachta indica against Nω-Nitro-L-Arginine Methyl Ester (L-NAME) induced hypertension and cardiorenal dysfunction in rats. Fifty (50) Wistar albino rats were grouped into five groups. Group A, the control, was administered potable water. Groups B-E received orally, 40 mg/kg of L-NAME only, 40 mg/kg of L-NAME and 100 mg/kg of AI extract, 40 mg/kg of L-NAME and 200 mg/kg of AI extract, and 40 mg/kg of L-NAME and 25 mg/kg of captopril, respectively for 21 days. The results of the present study revealed that L-NAME administration led to a significant increase in systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. Markers of oxidative stress (malondialdehyde,protein carbonyl) increased significantly while there was reduction in reduced glutathione level, activities of superoxide dismutase, glutathione peroxidase and glutathione-S-transferase as well nitric oxide bioavailability. Immunohistochemistry revealed higher expressions of nuclear factor kappa beta (NF-kB) and kidney injury molecule 1(Kim-1) and lower expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) in hypertensive rats. Our results indicated that with PRF of AI restored high blood pressure, reduced markers of oxidative stress, normalized serum NO bioavailability and increased the expressions of Nrf2. Hence, PRF of Azadirachta indica could be used for the treatment of hypertension.


Psidium guajava: A Single Plant for Multiple Health Problems of Rural Indian Population.
The rural population in India faces a number of health problems and often has to rely on local remedies. Psidium guajava Linn. (guava), a tropical plant which is used as food and medicine can be used by rural communities due to its several medicinal properties. A literature search was undertaken to gauge the rural health scenario in India and compile the available literature on guava so as to reflect its usage in the treatment of multiple health conditions prevalent in rural communities. Towards this, electronic databases such as Pubmed, Science Direct, google scholar were scanned. Information on clinical trials on guava was obtained from Cochrane Central Register of Controlled Trials and Clinicaltrial.gov. The literature survey revealed that guava possesses various medicinal properties which have been reported from across the globe in the form of ethnobotanical/ethnopharmacological surveys, laboratory investigations and clinical trials. Besides documenting the safety of guava, the available literature shows that guava is efficacious against the following conditions which rural communities would encounter. (a) Gastrointestinal infections; (b) Malaria; (c)Respiratory infections; (d) Oral/dental infections; (e) Skin infections; (f) Diabetes; (g) Cardiovascular/hypertension; (h) Cancer; (i) Malnutrition; (j) Women problems; (k) Pain; (l) Fever; (m) Liver problems; (n) Kidney problems. In addition, guava can also be useful for treatment of animals and explored for its commercial applications. In conclusion, popularization of guava, can have multiple applications for rural communities.


Long-term regulation of aquaporins in the kidney.
The discovery of the aquaporin family of water channels has greatly improved our understanding of how water crosses epithelial cells, particularly in the kidney. The study of the mechanisms involved in the regulation of collecting duct water permeability, in particular, has advanced very rapidly since the identification and characterization of aquaporin-2 (AQP2) in 1993. One of the more surprising findings has been the dramatic long-term changes that are seen in the abundance of this protein, as well as the recognition that these changes represent a way of modulating the acute antidiuretic effects of vasopressin. Furthermore, such changes seem to be of etiological and pathological significance in a number of clinical disorders of water balance. This review focuses on the various conditions in which AQP2 expression is altered (either increased or decreased) and on what this can tell us about the signals and mechanisms controlling these changes. Ultimately, this may be of great value in the clinical management of water balance disorders. Evidence is also now beginning to emerge that there are similar changes in the expression of other renal aquaporins, which had previously been thought to provide an essentially constitutive water permeability pathway, suggesting that they too should be considered as regulatory factors in the control of body water balance.


[Immunoglobulins and non-organ-specific antibodies in alcoholic liver cirrhosis].
The quantitative alterations of serum immunoglobulins and their relationship with functional liver alterations, and the incidence of non organ-specific antibodies have been studied in patients with alcoholic cirrhosis. The study was performed in 52 patients with alcoholic cirrhosis, and 30 healthy subjects were used as controls. Main findings were: increased serum IgA, IgG, and IgM in cirrhosis (p less than 0.001), increased IgA in liver failure (p less than 0.005), and increased IgM in patients with portal hypertension (p less than 0.001). Regarding non organ-specific antibodies, antinuclear antibodies were found in 28 % of the cases, and anti-smooth muscle antibodies in 9 %. No relationship could be established between antibody positivity and quantitative alterations of the serum immunoglobulins.


Development of longitudinal patterns in the cerebellum of the chicken (Gallus domesticus): a cytoarchitectural study on the genesis of cerebellar modules.
The cytoarchitecture of the cerebellum has been studied in chicken embryos from day 3-20 using serial sections stained with cresylviolet, haematoxylin-eosin and toluidine blue. Three periods have been distinguished in cerebellar development on a basis of cytoarchitectonic characteristics. Of these periods the middle one, which lasts from the 8th to the 15th day, is marked by two subsequent transient longitudinal cytoarchitectonic patterns in the cortical anlage. The first pattern, which exists between days 8 and 11, consists of 4 longitudinal Purkinje cell clusters (of the first order) at either side of the midline. The second pattern, which is most distinct and complete during embryonic days 12-14, is caused by specific localizations of otherwise few, early inwardly migrating granule cells from the external cerebellar matrix (so-called granule raphes), which pass through the layer of Purkinje cell clusters of the first order and thus subdivide these latter into smaller entities: Purkinje cell clusters of the second order. The number of these latter (6 or 7 and 11 or 12 in the anterior and posterior lobes, respectively) correspond to the number of parasagittal modules, which can be discerned on a basis of the organization of fiber connections of the adult cerebellar cortex. Thanks to this similarity various hypotheses can be formulated concerning the significance of the transient cytoarchitectonic patterns in the primitive cortex for the genesis of the modular organization of the cerebellum.


Leiomyoepithelioma of iris pigment epithelium.
A 4-year-old boy had a jet-black, nodular lesion growing in his right iris. Detailed clinical and histopathologic studies of this unusual tumor showed the lesion to be derived from the anterior iris pigment epithelium. The tumor cells appeared to be benign and exhibited characteristics of both pigment epithelium and smooth muscle. We have called this tumor "leiomyoepithelioma of iris pigment epithelium."


A prospective randomized study of a collar versus a collarless femoral prosthesis.
A prospective, randomized study of 44 collared versus 40 collarless cemented HD-2 total hip arthroplasties (THAs) was performed in 84 patients. Seventy patients were examined at an average of 4.6 years after surgery. Five hips have required, or are scheduled to have, revision arthroplasty: two with collared prostheses and three with collarless prostheses. Good collar contact with the proximal medial femur was achieved in 47% of the collared prostheses. No patient with good contact has required or is scheduled to have revision hip surgery. Radiolucent lines were greater in both frequency and width in Gruen Zones 2 and 7 in patients with a collarless prosthesis. Loss of endosteal height of the femoral neck was 3.5 mm in patients with collarless prostheses and 1.7 mm in patients with collared prostheses. Loss in height of the femoral neck was 2.6 mm in patients with collared prostheses with poor bone contact and 0.7 mm in patients with collared prostheses with good bone contact. The mean preoperative and postoperative Harris hip scores for the collarless group and for the collared group were not statistically different. There were no statistically significant differences in acetabular position, the incidence of acetabular radiolucent lines, or femoral subsidence between patients treated with collared or collarless prostheses. This study demonstrates that it is possible to stress the proximal medial portion of the femur with a collared prosthesis. Furthermore, a significant increase is identified in both the frequency and width of radiolucent lines in patients with collarless prostheses in Zones 2 and 7.(ABSTRACT TRUNCATED AT 250 WORDS)


[Perineal pain and involvement of the internal pudendal nerves].
A number of chronic pain syndromes in the perineal area can be related to pudental nerves suffering. The constancy of symptoms among various patients, and in duration for a particular one, alterations revealed by electrophysiologic studies, pain relief by diagnostic blocks, data from anatomic studies, preliminary results of medical and surgical applied therapies, give consistent arguments for possible organic lesions of pudental nerves.


Prion Protein Overexpression in Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Effectively Protected Rodent Kidney Against Ischemia-Reperfusion Injury Via Enhancing ATP/Mitochondrial Biogenesis-Role of ADMSC Rejuvenation and Proliferation.
We tested the hypothesis that overexpression of cellular-prion-protein in adipose-derived mesenchymal stem cells (PrPCOE-ADMSCs) effectively protected the kidney against ischemia-reperfusion (IR) injury in rat. Part I of cell culture was categorized into A1(ADMSCs)/A2(ADMSCs+p-Cresol)/A3(PrPCOE in ADMSCs)/A4 (PrPCOE in ADMSCs+p-Cresol). Part II of cell culture was divided into B1(ADMSCs)/B2[ADMSCs+lipopolysaccharide (LPS)]/B3(PrPCOE in ADMSCs)/B4(PrPCOE in ADMSCs+LPS). Sprague-Dawley (SD) rats (n = 50) were equally categorized into groups 1 (sham-operated-control)/2 (IR)/3 (IR+ADMSCs/6.0 × 105 equally divided into bilateral-renal arteries and 6.0 × 105 intravenous administration by 1 h after IR)/4 [IR+PrPCOE-ADMSCs (identical dosage administered as group 3)]/5 [IR+silencing PRNP -ADMSCs (identical dosage administered as group 3)], and kidneys were harvested post-day 3 IR injury. Part I results demonstrated that the cell viability at 24/48/72 h, BrdU uptake/number of mitDNA/APT concentration/mitochondrial-cytochrome-C+ cells and the protein expressions of ki67/PrPC at 72 h-cell culturing were significantly higher in PrPCOE-ADMSCs than in ADMSCs (all P < 0.001). The protein expressions of oxidative-stress (NOX-1/NOX2/NOX4/oxidized protein)/mitochondrial-damaged (p22-phox/cytosolic-cytochrome-C)/inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers were lowest in A1/A3 and significantly higher in A2 than in A4 (all P < 0.001). Part II result showed that the protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers exhibited an identical pattern of part I among the groups (all P < 0.001). The protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized-protein)/mitochondrial-damaged (cytosolic-cytochrome-C/p22-phox)/apoptotic (cleaved caspase-3/cleaved-PARP/mitochondrial-Bx)/autophagic (beclin-1/ratio of LC3B-II/LC3B-I)/fibrotic (Smad3/TGF-ß) biomarkers and kidney-injury-score/creatinine level were lowest in group 1, highest in group 2, significantly higher in group 5 than in groups 3/4 (all P < 0.0001). PrPCOE in ADMSCs rejuvenated these cells and played a cardinal role on protecting the kidney against IR injury.


Interactions of Neuronally Induced Stem Cells from Apical Papilla Spheres, Stems Cells from Apical Papilla, and Human Umbilical Vascular Endothelial Cells on Vasculogenesis and Neurogenesis.
Stem cell-based dental pulp regeneration has been extensively studied, mainly focusing on exploiting dental stem cells' osteogenic and angiogenic potentials. Dental stem cells' neurogenic role is often overlooked. Stem cells from apical papilla (SCAPs), originating from the neural crest and capable of sphere formation, display potent neurogenic capacity. This study aimed to investigate the interactions of neuronally induced stem cells from apical papilla (iSCAP) spheres, SCAPs, and human umbilical vascular endothelial cells (HUVECs) on vasculogenesis and neurogenesis. SCAPs were isolated and characterized using flow cytometry and multilineage differentiation assays. SCAP monolayer culture and spheres were neuronally induced by a small molecule neural induction medium, and the neural gene expression and neurite formation at days 0, 3, and 7 were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and using phase-contrast light and fluorescence microscopy. Direct coculture or pulp-on-chip was used to investigate iSCAP sphere interaction with SCAPs and HUVECs. RT-qPCR, fluorescence microscopy, and immunostaining with β-tubulin III, alpha-smooth muscle actin, and CD31 were used to study neural gene expression, neurite formation, and neurovascular cell interactions. Neural induction medium with small molecules rapidly induced SCAP differentiation toward neural-like cells. Gene expression of Nestin, β-tubulin III, microtubule-associated protein 2, neuron-specific enolase, and NeuN was higher in iSCAP spheres than in iSCAPs. iSCAP spheres formed more and longer neurites compared with iSCAPs. iSCAP sphere, HUVEC, and SCAP direct coculture significantly enhanced vessel formation along with up-regulated VEGF (P < .001) and multiple neural markers, such as Nestin (P < .01), microtubule-associated protein 2 (P < .001), S100 (P < .001), and NG2 (P < .001). iSCAP spheres, SCAPs, and HUVECs cultured in a pulp-on-chip system promoted endothelial and neural cell migration toward each other and alpha-smooth muscle actin-positive and CD31-positive cells assembling for the vascular constitution. iSCAP-formed spheres interact with SCAPs and HUVECs, promoting vasculogenesis and neurogenesis.


Intracameral injection of a chemically cross-linked hydrogel to study chronic neurodegeneration in glaucoma.
Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ± 3 and 24 ± 3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.


Limitations of peptide retro-inverso isomerization in molecular mimicry.
A retro-inverso peptide is made up of d-amino acids in a reversed sequence and, when extended, assumes a side chain topology similar to that of its parent molecule but with inverted amide peptide bonds. Despite their limited success as antigenic mimicry, retro-inverso isomers generally fail to emulate the protein-binding activities of their parent peptides of an alpha-helical nature. In studying the interaction between the tumor suppressor protein p53 and its negative regulator MDM2, Sakurai et al. (Sakurai, K., Chung, H. S., and Kahne, D. (2004) J. Am. Chem. Soc. 126, 16288-16289) made a surprising finding that the retro-inverso isomer of p53(15-29) retained the same binding activity as the wild type peptide as determined by inhibition enzyme-linked immunosorbent assay. The authors attributed the unusual outcome to the ability of the D-peptide to adopt a right-handed helical conformation upon MDM2 binding. Using a battery of biochemical and biophysical tools, we found that retro-inverso isomerization diminished p53 (15-29) binding to MDM2 or MDMX by 3.2-3.3 kcal/mol. Similar results were replicated with the C-terminal domain of HIV-1 capsid protein (3.0 kcal/mol) and the Src homology 3 domain of Abl tyrosine kinase (3.4 kcal/mol). CD and NMR spectroscopic as well as x-ray crystallographic studies showed that D-peptide ligands of MDM2 invariably adopted left-handed helical conformations in both free and bound states. Our findings reinforce that the retro-inverso strategy works poorly in molecular mimicry of biologically active helical peptides, due to inherent differences at the secondary and tertiary structure levels between an l-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structure level.


An Assessment of Three Post-Discharge Drug-Based Quality Assurance Events for Elderly Medicare Beneficiaries Enrolled in a Stand-Alone Part D Plan.
This article examines the distribution of drug-based quality assurance events (QAEs) post-discharge across five-day increments and identifies characteristics associated with post-discharge QAEs. Data were obtained through a cross-sectional study of Medicare beneficiaries age 65 and over enrolled in stand-alone Part D plans during calendar year 2010. Our findings suggest an even more compressed timeframe than previously identified in the literature for addressing medication issues among elderly beneficiaries. Specifically, medication reconciliation is needed within two to three days of discharge instead of within 14 days as the literature suggests. To decrease inadvertent readmissions, an immediate in-community medication reconciliation following hospital discharge is needed.


Phase-shift-keying and on-off-keying with improved performances using electroabsorption modulators with interferometric effects.
We present methods of optical modulation employing electroabsorption in an interferometric structure. The interferometric operation enables electroabsorption modulators for phase-shift keying and allows generation of on-off-keying signals with much improved extinction ratios. We demonstrate 40-Gb/s phase-shift-keying modulation, and up to 8.7 dB improvement in extinction ratio in 40-Gb/s on-off-keying modulation with 0.8V driving voltage using a commercial electroabsorption modulator. Methods of applying electroabsorption modulators for high spectral-efficiency formats generation are also proposed.


Postinjury depression is a serious complication in adolescents after major trauma: injury severity and injury-event factors predict depression and long-term quality of life deficits.
Little is known about the impact of postinjury depression after major trauma in adolescents. A prospective epidemiologic study was conducted to examine depression in injured adolescents. Specific objectives of this report are to identify risk factors for depression onset and the impact of depression on quality of life (QoL) outcomes. Four hundred one trauma patients were enrolled in this study (age, 12-19 years; injury severity score [ISS] ≥4). Depression diagnosis was based on the Children's Depression Inventory. QoL outcomes were measured using the Quality of Well-being Scale at 3-, 6-, 12-, 18-, and 24-month follow-up. Depression at discharge was diagnosed in 41% of 399 adolescent trauma survivors with complete Children's Depression Inventory data. Multivariate logistic regression identified ISS, >3 body regions injured, low socioeconomic status, family members injured at the scene, and suicidal ideology or attempted suicide before injury as strong and independent predictors of depression risk. ISS and three or more body regions injured predicted depression risk. Patients with severe injury (ISS ≥17) were twice more likely to have depressive symptoms than patients with moderate injury (ISS <17; odds ratio [OR] = 2.0; p < 0.01). Patients with three or more body regions injured were more likely to have depressive symptoms than patients with less than three body regions injured (OR = 2.1; p < 0.01). Adolescents from low socioeconomic status families were more likely to be depressed (OR = 2.2; p < 0.05). Adolescent patients who witnessed family injured at the trauma event were also more likely to be depressed (OR = 2.4; p < 0.01). Patients who experienced suicidal ideology or attempted suicide preinjury were more likely to be depressed than adolescent patients who did not (OR = 2.87; p < 0.05). Quality of well-being scores were significantly and markedly lesser for patients with depression across the 24-month follow-up (3-18 months follow-up, p < 0.0001; 24 months: with depression = 0.738 vs. without depression = 0.784, p < 0.0001). Patients with depression were also significantly more likely to develop acute stress disorder and long-term posttraumatic stress disorder (OR = 1.8, p < 0.001). Postinjury depression is a major and an important complication in seriously injured adolescents. Adolescent trauma survivors have high rates of predischarge depression. Depression severely impacts QoL outcomes and is associated with injury severity, injury event-related factors, social factors, acute stress disorder, and posttraumatic stress disorder. Early recognition and treatment of DEPR in seriously injured adolescents will improve acute trauma care and long-term QoL outcomes.


Optimizing practice through research: a new perspective to solve an old problem.
Policy makers, researchers, clinicians, and the public are frustrated that research in the health sciences has not resulted in a greater improvement in patient outcomes. Our experience as clinicians and researchers suggests that this frustration could be reduced if health sciences research were directed by 5 broad principles: (1) the needs of patients and populations determine the research agenda; (2) the research agenda addresses contextual and implementation issues, including the development of delivery and accountability systems; (3) the research agenda determines the research methods rather than methods determines the research agenda; (4) researchers and clinicians collaborate to define the research agenda, allocate resources, and implement findings; and (5) the level of funding for implementation research is commensurate with and proportional to the magnitude of the task. To keep the research agenda focused on the task of improving health and to acknowledge that the effort must be seen as more comprehensive than translating or transferring research into practice (TRIP), we suggest that the task be reframed, using the term optimizing practice through research.


Allograft Bone as Antibiotic Carrier.
The treatment of chronic bone and joint infections is characterized by obstinate persistency of the causing microorganisms and resulting long term disability to patients, associated with remarkable costs for the health care system. Difficulties derive from biofilm formed on dead bone and eventual implants, with resistance against immunological defences and antimicrobial substances. Biofilm embedded bacteria require up to 1000 times the antibiotic concentration of planktonic bacteria for elimination. Systemic antibiotic treatment alone cannot provide the concentrations required and surgical intervention is always prerequisite for potentially providing a cure. A second issue is that osseous defects are almost always present after surgical debridement, and it is difficult to address their reconstruction. One option is to use bone grafts, either from the patient´s own body or from foreign donors (allografts). Grafts are usually unvascularized and are prone to colonization with bacteria. Loading of allografts with antibiotics may not only protect grafts from bacterial adhesion but, using appropriate processing methods, may also provide high local antibiotic concentrations that may eliminate remaining sessile pathogens. For efficient action as antibiotic carriers, the release of antibiotics should be above the minimum biofilm eradication concentration (MBEC) for a prolonged period of time. Cleaning the bone from bone marrow opens a large reservoir for storage of antimicrobial substances that, after implantation, may be released to the surrounding in a sustained mode, possibly eliminating remaining biofilm remnants. Removal of bone marrow, leaving a pure matrix, provides increased safety and improved revascularization of the graft. Local provision of antibiotic concentrations above the MBEC may enable simultaneous internal fixation with osteosynthetic material and single stage exchange of infected endoprostheses, resulting in shorter hospital stays with reduced pain and faster rehabilitation of patients.


Addressing the challenges, barriers, and enablers to physical activity participation in priority women's groups.
The Women's Active Living Kits (WALK) Pilot Program was an Australian federal government initiative designed to identify an effective model for extending physical activity participation in government identified priority women's groups. The purpose of this study is to address the barriers and challenges to physical activity participation in selected priority women's groups and present possible strategies to assist with engaging these groups in physical activity. Ten focus group evaluation sessions were undertaken with priority women's groups who took part in the WALK program. Participants were encouraged to share their opinions, perceptions and beliefs regarding their physical activity behaviors, in a semistructured, open table discussion. Participants reported a number of psychological and cognitive, sociocultural, and environmental factors which restricted their participation in physical activity. Participants also highlighted strategies they felt would enable physical activity participation. These findings are valuable and should be used as a platform to inform the design and implementation of future physical activity interventions for priority women's groups.


The distribution of actin cables and microtubules in hybrids between malignant and non-malignant cells, and in tumours derived from them.
Cell fusion provides a genetic test for linkage between cellular phenotypic markers and malignancy. We have examined hybrid cells in which malignancy is suppressed and malignant segregants derived from them, to test whether the reappearance of malignancy is regularly associated with loss or abnormality of actin cables or microtubules. Immunofluorescence studies did not reveal any difference between the malignant and non-malignant hybrids in the number and distribution of microtubules that they contained. All the hybrids, whether tumorigenic or not, contained elaborate patterns of cytoplasmic microtubules. Furthermore, no consistent relationship was observed between the absence of actin cables and malignancy.


Risk factors for breast cancer in a black population--the Barbados National Cancer Study.
The Barbados National Cancer Study (BNCS) is a nationwide case-control study investigating environmental and genetic factors for breast cancer (BC) in a predominantly African-origin population with similar ancestry as African-Americans. This report evaluates associations of incident BC in the BNCS to various factors, including demographic, anthropometric, reproductive and family history variables, not investigated previously in this population. The BNCS included 241 incident BC cases and 481 age-matched female controls, with mean ages of 57 and 56 years, respectively. In addition to a reported family history of BC in a close relative [odds ratios (OR) = 3.74, 95% CI (1.41, 9.90) in a parent; OR = 3.26 (1.47, 7.21) in a sibling], other factors associated with BC were older age at first full-term pregnancy [OR = 1.04 (1.00, 1.07)] and having a history of benign breast disease [OR = 1.88 (1.19, 2.99)]. Increased parity reduced the risk of BC [OR = 0.34 (0.15, 0.77) among those with >or=3 children]. The reproductive patterns of African-Barbadian (AB) women tended to differ from those of African-American (AA) women (later age of menarche, earlier age at first pregnancy, higher frequency of lactation and infrequent use of exogenous hormones) and could help to explain their considerably lower postmenopausal incidence of BC. The relationship between reported family history and BC, combined with the associations noted for several reproductive and other variables, supports the genetic and environmental contributions to BC, which may vary in populations across the African diaspora. Further investigations of other populations may clarify these issues.


Robust metric for quantifying the importance of stochastic effects on nanoparticle growth.
Comprehensive representation of nanoparticle dynamics is necessary for understanding nucleation and growth phenomena. This is critical in atmospheric physics, as airborne particles formed from vapors have significant but highly uncertain effects on climate. While the vapor-particle mass exchange driving particle growth can be described by a macroscopic, continuous substance for large enough particles, the growth dynamics of the smallest nanoparticles involve stochastic fluctuations in particle size due to discrete molecular collision and decay processes. To date, there have been no generalizable methods for quantifying the particle size regime where the discrete effects become negligible and condensation models can be applied. By discrete simulations of sub-10 nm particle populations, we demonstrate the importance of stochastic effects in the nanometer size range. We derive a novel, theory-based, simple and robust metric for identifying the exact sizes where these effects cannot be omitted for arbitrary molecular systems. The presented metric, based on examining the second- and first-order derivatives of the particle size distribution function, is directly applicable to experimental size distribution data. This tool enables quantifying the onset of condensational growth without prior information on the properties of the vapors and particles, thus allowing robust experimental resolving of nanoparticle formation physics.


Neochloris aquatica induces larval mortality, molting defects, and unstable flightless adults in the Asian tiger mosquito.
The Asian tiger mosquito, Aedes albopictus, is a highly invasive and aggressive species capable of transmitting a large number of etiological agents of medical and veterinary importance, posing a high risk for the transmission of emerging viruses between animals and humans. In this work, we evaluated the mosquitocidal activity of Neochloris aquatica against A. albopictus throughout its development and analyzed whether this effect was potentiated when the microalga was cultivated under stress conditions due to nutrient deprivation. Our results suggest that N. aquatica produces metabolites that have negative effects on these insects, including larval mortality, interruption of pupal development, and incomplete emergence of adults when fed on microalgae in the larval stages. When microalgae were cultured under stress conditions, an increase in molting defects was recorded, and the number of healthy adults emerged drastically decreased. Histological studies revealed severe signs of total disintegration of different tissues and organs in the thorax and abdomen regions. The muscles and fat bodies in the midgut and foregut were severely distorted. In particular, larval intestinal tissue damage included vacuolization of the cytoplasm, destruction of brush border microvilli, and dilation of the intercellular space, which are distinctive morphological characteristics of apoptotic cells. Evidence suggests that N. aquatica produces metabolites with mosquitocidal effects that affect development and, therefore, the ability to vector etiological agents of medical and veterinary importance.


Quantitative flow cytometric monitoring of invasion of epithelial cells by Mycobacterium tuberculosis.
Current methods for evaluating mycobacterial invasion of target cells pose technical difficulties including a long turn-around time. Thus, new methodologies must be developed that allow rapid and reliable monitoring of host cell invasion. Here, the invasion of A549 cell line by SYBR safe-labeled Mycobacterium tuberculosis (M. tuberculosis) H37Rv was assessed by flow cytometry and was expressed as the percentage of cells infected by M. tuberculosis. Over a third of A549 cells were invaded by M. tuberculosis, two hours after infection. The specificity of the invasion was confirmed in assays using red blood cells as target cells and Escherichia coli as the non-invasive bacterial control. These findings show that invasion of pulmonary epithelial cells by M. tuberculosis can rapidly and quantitatively be assessed with a great sensitivity by flow cytometric detection of SYBR safe-labeled M. tuberculosis.


Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2-ethylhexanoic acid.
We have found here that there are clear structural requirements for peroxisome proliferation (monitored as increases in carnitine acetyltransferase activity, cyanide-insensitive palmitoyl-CoA oxidation, catalase and increases in the protein designated PPA 80) in mouse liver. From the investigation of ten structural analogues of 2-ethylhexanoic acid, it could be concluded that the most effective proliferators all have an ethyl group as the substituent on carbon 2 of the main chain, which consists of six carbons. The further observation from this group of compounds that a charged group is required for effective proliferation leads us to speculate that such a group is involved in the molecular mechanism as well. Many, but not all, of the effective peroxisome proliferators in a second group of compounds contain a phenoxy group, often with a substituted alpha carbon. Interestingly, the 2,4-dichlorophenoxyacetic and 2,4,5-trichlorophenoxyacetic acids are both effective peroxisome proliferators, but the closely related p-chlorophenoxyacetic acid is inactive in this respect, indicating that the chlorine atom at position 2 must be essential to the process in these cases. The results presented here also indicate that the structural requirements for proliferation of mitochondria are similar to those for proliferation of peroxisomes. Certainly, the most effective peroxisome proliferators also cause large increases in 'mitochondrial' protein and cytochrome oxidase activity, i.e. there is an obvious qualitative correlation.


Lung cancer in pregnancy.
In the 26th week of gestation, a 29-year-old pregnant office employee was referred to the pulmonary department of Linz General Hospital (AKH) under the suspicion of tuberculosis. She complained of a cough with intermittent hemoptysis and pain in the thoracic spine from which she had been suffering the past 9 weeks. A plain chest X-ray showed a dense infiltrate on the right side and multiple smaller shadows in both lungs. Laboratory testing revealed anemia, leukocytosis, and an increase of C-reactive protein. All tests for tuberculosis were negative.A bronchoscopy was performed and biopsies were taken from the right upper and middle lobe. The histopathological examination found cells of an adenocarcinoma. A magnetic resonance imaging (MRI) revealed a large tumor and surrounding atelectasis were seen in the right upper and middle lobe, as well as multiple intrapulmonary metastases in both lungs. In addition, not only metastases in the thoracic spine (level Th2/3) but also at other osseous locations and multiple cerebral metastases were detected. The patient received one cycle of chemotherapy consisting of docetaxel and carboplatin (AUC5) in the 27th week of gestation. Additional radiotherapy was applied to the involved thoracic spine. Due to positive epidermal growth factor receptor mutation, therapy with gefitinib 250 mg/day was started 2 days after a Caesarean section (preceded by treatment for fetal lung maturation). A healthy girl was delivered in the 30th week of pregnancy. Staging with computed tomography (CT) after delivery revealed an unstable fracture of Th2 with compression of the spinal cord. Neurosurgery was performed, consisting of a ventral corporectomy of Th1-2 followed by an anterior and posterior osteosynthesis for stabilization. The patient was discharged without neurological deficits within 1 week. Subsequent treatment with gefitinib improved the performance status of the patient, and CT scans of the chest and an MRI of the brain showed the size of the tumor to be shrinking. Meanwhile, the infant developed appropriately for her age.After 14 months of the first diagnosis, the patient experienced neurological symptoms (aphasia, confusion) due to neoplastic meningeosis and cerebral venous sinus thrombosis together with local tumor progression in the lung. One course of chemotherapy, combining carboplatin/pemetrexed/bevacizumab, was given without clinical response. Despite best supportive care, the patient died 17 months after diagnosis in October 2013.


Acute and chronic hypertensive headache and hypertensive encephalopathy.
Three patients are described who experienced headache from hypertension: one had acute headache from acute hypertension, one had daily, morning headaches from chronic hypertension, and one had acute headache with generalized tonic-clonic seizure from hypertensive encephalopathy. The presumed pathophysiological mechanisms involved in the three hypertensive headache conditions are reviewed.


Compliance with gastric cancer guidelines is associated with improved outcomes.
Limited data are available on the implementation and effectiveness of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer. We sought to assess rates of compliance with NCCN Guidelines, specifically stage-specific therapy during the initial episode of care, and to determine its impact on outcomes. The California Cancer Registry was used to identify cases of gastric cancer from 2001 to 2006. Logistic regression and Cox proportional hazard models were used to predict guideline compliance and the adjusted hazard ratio for mortality. Patients with TNM staging or summary stage (SS) were also analyzed separately. Compliance with NCCN Guidelines occurred in just 45.5% of patients overall. Patients older than 55 years were less likely to receive guideline-compliant care, and compliance was associated with a median survival of 20 versus 7 months for noncompliant care (P<.001). Compliant care was also associated with a 55% decreased hazard of mortality (P<.001). Further analysis revealed that 50% of patients had complete TNM staging versus an SS, and TNM-staged patients were more likely to receive compliant care (odds ratio, 1.59; P<.001). TNM-staged patients receiving compliant care had a median survival of 25.3 months compared with 15.1 months for compliant SS patients. Compliance with NCCN Guidelines and stage-specific therapy at presentation for the treatment of patients with gastric cancer was poor, which was a significant finding given that compliant care was associated with a 55% reduction in the hazard of death. Additionally, patients with TNM-staged cancer were more likely to receive compliant care, perhaps a result of having received more intensive therapy. Combined with the improved survival among compliant TNM-staged patients, these differences have meaningful implications for health services research.


Control yourself: alcohol and impulsivity.
Impulsivity represents a complex, multifaceted construct with relevance to alcohol use, abuse, and dependence. Researchers are refining the definitions and assessment of different subtypes of impulsive behavior and relating these to the causes and consequences of alcohol-related behaviors and disorders. A satellite symposium on alcohol and impulsivity was held at the 2009 convention of the Research Society on Alcoholism. This article provides an overview of the rationale for the symposium, a synopsis of review and original research articles emanating from the symposium, and a description of the implications of the work and possible future research directions.


Treatment of nonpsychotic major depression during pregnancy: patient safety and challenges.
In pregnant women with major depression, the overarching goal of treatment is to achieve or maintain maternal euthymia, thus limiting both maternal and fetal exposure to the harmful effects of untreated or incompletely treated depression. However, the absence of uniformly effective therapies with guaranteed obstetric and fetal safety makes the treatment of major depression during pregnancy among the most formidable of clinical challenges. Clinicians and patients are still faced with conflicting data and expert opinion regarding the reproductive safety of antidepressants in pregnancy, as well as large gaps in our understanding of the effectiveness of most antidepressants and nonpharmacological alternatives for treating antenatal depression. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated maternal depression during pregnancy, the effectiveness of interventions for maternal depression during pregnancy, and potential obstetric, fetal, and neonatal risks associated with antenatal antidepressant use.


School-based practice: acquiring the knowledge and skills.
The purpose of this descriptive study is to investigate the perceptions of occupational therapists working in school-based settings regarding their level of preparation for practice. The Survey of School-Based Practice was mailed to 1,102 occupational therapists working in school-based practice (SBP) throughout the United States. The mailing was based on a random sampling of 20% of the School System Special Interest Section of the American Occupational Therapy Association. Results were based on 450 returned completed surveys representing a response rate of 41%. The results were analyzed according to the respondents years of experience in SBP, entry (less than 3 years), transitioning from another practice setting with less than 1 year in SBP, and experienced with 3 or more years experience in SBP. The results indicated the majority of occupational therapists perceive themselves to be poorly prepared for this practice area based on entry-level education alone. Statistically significant differences were seen between continuing education needs and level of experience in SBP. Continuing education and mentoring were most often listed by therapists as preparing them for SBP Implications for the profession are discussed.


[Basic research during residency in Israel: is change needed?].
A six-month research period is a mandatory part of the residency training program in most basic specialties in Israel and is named: the "basic science period". This is the only period in an Israeli physician's medical career which is dedicated strictly to research, accentuating the importance of medical research to the quality of training and level of medicine in Israel. From another point of view, one may argue that in an era of shortage of physicians on the one hand and the dizzying rate of growth in medical knowledge on the other hand, every moment spent training in residency is precious, therefore, making the decision of whether to dedicate six months for research becomes ever more relevant. This question is currently raised for discussion once again by the Scientific Council of the Israeli Medical Association. The Scientific Council lately issued a call for comments sent to all Israeli physicians, asking their opinion on several key questions regarding basic science research. Learning the public's opinion will serve as a background for discussion. A total of 380 physicians responded to the call and specified their standpoint on the subject, among them heads of departments, units and clinics, senior physicians and residents. The findings pointed to strong support in maintaining the research period as part of residency training due to its importance to medical training and medicine, although half the respondents supported the use of various alternative formats for research together with the existing format. Those alternative format suggestions will be thoroughly reviewed. A smaller group of respondents supported allowing residents a choice between two tracks--with or without a research period, and only a few were in favor of canceling the research requirement altogether. The writers maintain that the "basic science period" of research during residency training is vital and its contribution to the high level of specialists and high level of medicine requires its conservation. Nevertheless, alternative formats which might be suitable for some residents should be considered, and auxiliary tools to help residents fulfill their potential in research and raise the quality of written research papers should be constructed.


Testicular volume in infertile versus fertile white-European men: a case-control investigation in the real-life setting.
Testicular volume (TV) is considered a good clinical marker of hormonal and spermatogenic function. Accurate reference values for TV measures in infertile and fertile men are lacking. We aimed to assess references values for TV in white-European infertile men and fertile controls. We analyzed clinical and laboratory data from 1940 (95.0%) infertile men and 102 (5.0%) fertile controls. Groups were matched by age using propensity score weighting. TV was assessed using a Prader orchidometer (PO). Circulating hormones and semen parameters were investigated in every male. Descriptive statistics, Spearman's correlation, and logistic regression models tested potential associations between PO-estimated TV values and clinical variables. Receiver operating characteristic (ROC) curves were used to find TV value cutoffs for oligoasthenoteratozoospermia (OAT) and nonobstructive azoospermia (NOA) status in infertile men. The median testicular volume was smaller in infertile than that of fertile men (15.0 ml vs 22.5 ml; P < 0.001). TV positively correlated with total testosterone, sperm concentration, and progressive sperm motility (all P ≤ 0.001) in infertile men. At multivariable logistic regression analysis, infertile status (P < 0.001) and the presence of left varicocele (P < 0.001) were associated with TV < 15 ml. Testicular volume thresholds of 15 ml and 12 ml had a good predictive ability for detecting OAT and NOA status, respectively. In conclusion, infertile men have smaller testicular volume than fertile controls. TV positively correlated with total testosterone, sperm concentration, and progressive motility in infertile men, which was not the case in the age-matched fertile counterparts.


Effects of hexachlorocyclohexane isomers on the acquisition of kindled seizures.
The effects of three isomers (alpha, beta, gamma) of hexachlorocyclohexane on the acquisition and expression of kindled amygdaloid seizures were compared. Treatment with corn oil (vehicle) was compared with daily 5 mg/kg doses of the isomers for 15 days during kindling procedures. The results confirmed the proconvulsant action previously described for the gamma-HCH isomer (lindane). Alpha-HCH did not produce significant effects. Rats treated with beta-HCH exhibited delayed rates of kindling acquisition and less severe seizures. Exposure to beta-HCH (5, 10 and 20 mg/kg) daily produced a dose-dependent decrease in the rate of kindling acquisition, seizure severity and afterdischarge duration. The differences were still manifest during an additional 20 kindling trials after beta-HCH administration had stopped. It is concluded that significant differences exist among the isomers of HCH with respect to their effects on the mammalian central nervous system and their effect in the kindling model of epilepsy. The availability of stereoisomers possessing different actions on kindling should make these compounds useful for discriminating between non-specific changes induced in membranes or at binding sites and specific changes correlated with proconvulsant or anticonvulsant effects in the kindling model.


Occurrence of oral health problems and planned measures in dependent older people in nursing care.
To describe oral health problems and planned measures in older people receiving nursing care. Poor oral health conditions have a negative impact on the quality of life of older people. Therefore, oral care is an important task in daily nursing activities. Data were obtained from the web-based Swedish national quality register Senior Alert. Data regarding oral health status and planned measures in individuals ≥65 years from one county in Sweden between July 2014-June 2015 were included. The Revised Oral Assessment Guide-the Jönköping (ROAG-J) was used routinely by nursing staff in nursing care facilities to measure oral health status. Oral assessments were made on 2,567 individuals (65.7% women). The most common oral health problem was related to "Teeth" (43.0%), which indicates deficient oral hygiene and/or broken teeth. At least one measure was planned in all the participants. The most common planned measures were "Moistening of the mouth" (16.6%), followed by "Brushing - assistance or complete help" (13.5%). Oral health problems were common, and planned measures did not seem to be sufficient to address the identified problems. The results indicate that greater priority should be given to the oral health care of older people in nursing care. The study highlights the importance of not only identifying oral health problems but also having knowledge and strategies for oral health care. Collaboration is needed to support nurses in caring for the oral health care of older people in nursing homes.


[Features of the parasitic system of Ixodid ticks--Borrelia--small mammals in the Russian Northwest].
Mammals and ticks was collected in 1995-1997 years in Novgorod region from May to September. Traps were exposed during 5 consecutive days every month in 4 different biotopes. 928 hosts were captured during three years. 357 larvae and 59 nymphs of Ixodes persulcatus, 356 larvae and 71 nymphs of I. trianguliceps were collected. The Clethrionomys glareolus and Sorex araneus are main hosts of larvae of I. persulcatus and I. trianguliceps. C. glareolus feed 76.2% of I. persulcatus larvae and 25% of I. trianguliceps larvae, S. araneus--27.1 and 45.9% of larvae, respectively. The abundance of larvae and nymphs of I. persulcatus was 0.26 and 0.13 on C. glareolus, and 0.41, 0.08 on S. araneus; for I. trianguliceps this indices are 0.15 and 0.09, 0.95 and 0.13, respectively. Infection rate of larvae and nymphs I. persulcatus and I. trianguliceps with Borrelia burgdorferi s. l. was 94-100%, confirmed by IFA with H5332. The borreliemia was found in 13.6% G. glareolus, 6.6--Microtus arvialis, 4.2% Apodemus uralensis. For all species of sorex this index varied from 0.9 to 44.9% in different years. Increase of mammal's numbers with the borreliemia correlated with peaks of activity of larvae of I. persulcatus. Finding of Borrelia burgdorferi s. l. in I. trianguliceps indicates an occurrence of enzootic locuses.


Considering Mobility Status and Home Environment in Readmission Risk After Total Knee Arthroplasty.
Discharge disposition following total knee arthroplasty (TKA) offers varying levels of post-acute care monitoring depending on the medical status of the patient and his or her ability to function independently. Discharge disposition following TKA is associated with 30-day and 90-day hospital readmission, but prior studies have not consistently considered confounding due to mobility status after TKA, available caregiver support, and measures of home area deprivation. The purpose of this study was to examine 30-day and 90-day readmission risk for patients discharged to a skilled nursing facility (SNF) following TKA after controlling specifically for these factors, among other covariates. This was a retrospective cohort study of patients undergoing TKA at any of 11 hospitals in a single, large, academic health-care system between January 2, 2017, and August 31, 2022, who were discharged to an SNF or home health care (HHC). The adjusted relative risk of readmission within 30 and 90 days of discharge to an SNF compared with HHC was estimated using modified Poisson regression models. There were 15,212 patients discharged to HHC and 1,721 patients discharged to SNFs. Readmission within 30 days was 7.1% among patients discharged to SNFs and 2.4% among patients discharged to HHC; readmission within 90 days was 12.1% for the SNF group and 4.8% for the HHC group. The adjusted relative risk after discharge to an SNF was 1.07 (95% confidence interval [CI], 0.79 to 1.46; p = 0.65) for 30-day readmission and 1.45 (95% CI, 1.16 to 1.82; p < 0.01) for 90-day readmission. Discharge to an SNF compared with HHC was independently associated with 90-day readmission, but not with 30-day readmission, after controlling for mobility status after TKA, available caregiver support, and home Area Deprivation Index, among other covariates. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Removal of inflammatory ascites is associated with dynamic modification of local and systemic inflammation along with prevention of acute lung injury: in vivo and in silico studies.
Sepsis-induced inflammation in the gut/peritoneal compartment occurs early in sepsis and can lead to acute lung injury (ALI). We have suggested that inflammatory ascites drives the pathogenesis of ALI and that removal of ascites with an abdominal wound vacuum prevents ALI. We hypothesized that the time- and compartment-dependent changes in inflammation that determine this process can be discerned using principal component analysis (PCA) and Dynamic Bayesian Network (DBN) inference. To test this hypothesis, data from a previous study were analyzed using PCA and DBN. In that study, two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via intestinal ischemia/reperfusion and placement of a peritoneal fecal clot. The control group (n = 6) had the abdomen opened at 12 h after injury (T12) with attachment of a passive drain. The peritoneal suction treatment (PST) group (n = 6) was treated in an identical fashion except that a vacuum was applied to the peritoneal cavity at T12 to remove ascites and maintained until T48. Multiple inflammatory mediators were measured in ascites and plasma and related to lung function (PaO2/FIO2 ratio and oxygen index) using PCA and DBN. Peritoneal suction treatment prevented ALI based on lung histopathology, whereas control animals developed ALI. Principal component analysis revealed that local to the insult (i.e., ascites), primary proinflammatory cytokines play a decreased role in the overall response in the treatment group as compared with control. In both groups, multiple, nested positive feedback loops were inferred from DBN, which included interrelated roles for bacterial endotoxin, interleukin 6, transforming growth factor β1, C-reactive protein, PaO2/FIO2 ratio, and oxygen index. von Willebrand factor was an output in control, but not PST, ascites. These combined in vivo and in silico studies suggest that in this clinically realistic paradigm of sepsis, endotoxin drives the inflammatory response in the ascites, interplaying with lung dysfunction in a feed-forward loop that exacerbates inflammation and leads to endothelial dysfunction, systemic spillover, and ALI; PST partially modifies this process.


The effectiveness of health care provider physical activity recommendations in cancer survivors: a systematic review and meta-analysis protocol.
Cancer survivors face a range of negative physical and psychological effects that can be mitigated by participating in physical activity. Despite this, most do not meet recommended levels. Health care providers may be in a unique position to promote participation in physical activity among cancer survivors. The aim of this systematic review and meta-analysis is to synthesize the findings from randomized controlled trials and controlled clinical trials investigating the effectiveness of health care provider-administered physical activity recommendations on participation in physical activity among cancer survivors. Ten electronic databases (CINAHL, CENTRAL, Education Source, EMBASE, LILACS, MEDLINE, OTSeeker, PEDro, PsycINFO, SPORTDiscus) will be searched to identify relevant studies. The electronic searches will be supplemented by scanning the reference lists of relevant articles retrieved during these searches to ensure all potentially relevant studies are identified. Two reviewers will independently screen all titles and abstracts resulting from the searches to identify potentially eligible studies. They will then screen the full-text articles passing the first screen to identify studies for inclusion using predetermined inclusion/exclusion criteria, extract data from studies meeting all criteria, and assess the risk of bias of these studies. Results will be summarized narratively and statistically. By summarizing the best available evidence for the effectiveness of health care provider physical activity recommendations for increasing participation in physical activity among cancer survivors, the results of this systematic review and meta-analysis will help determine if making physical activity recommendations effectively changes cancer survivors behaviour. It will also help to identify knowledge gaps and highlight areas in need of additional research.


Sensitivity analysis for the interactive effects of internal bias and publication bias in meta-analyses.
Meta-analyses can be compromised by studies' internal biases (e.g., confounding in nonrandomized studies) as well as publication bias. These biases often operate nonadditively: publication bias that favors significant, positive results selects indirectly for studies with more internal bias. We propose sensitivity analyses that address two questions: (1) "For a given severity of internal bias across studies and of publication bias, how much could the results change?"; and (2) "For a given severity of publication bias, how severe would internal bias have to be, hypothetically, to attenuate the results to the null or by a given amount?" These methods consider the average internal bias across studies, obviating specifying the bias in each study individually. The analyst can assume that internal bias affects all studies, or alternatively that it only affects a known subset (e.g., nonrandomized studies). The internal bias can be of unknown origin or, for certain types of bias in causal estimates, can be bounded analytically. The analyst can specify the severity of publication bias or, alternatively, consider a "worst-case" form of publication bias. Robust estimation methods accommodate non-normal effects, small meta-analyses, and clustered estimates. As we illustrate by re-analyzing published meta-analyses, the methods can provide insights that are not captured by simply considering each bias in turn. An R package implementing the methods is available (multibiasmeta).


Surgery for degenerative lumbar spondylosis.
Surgical investigations and interventions account for large health care utilisation and costs, but the scientific evidence for most procedures is still limited. Degenerative conditions affecting the lumbar spine are variously described as lumbar spondylosis or degenerative disc disease (which we regarded as one entity) and may be associated with back pain and associated leg symptoms, instability, spinal stenosis and/or degenerative spondylolisthesis. The objective of this review was to assess current scientific evidence on the effectiveness of surgical interventions for degenerative lumbar spondylosis. We searched CENTRAL, MEDLINE, PubMed, Spine and ISSLS abstracts, with citation tracking from the retrieved articles. We also corresponded with experts. All data found up to 31 March 2004 are included. Randomised (RCTs) or quasi-randomised trials of surgical treatment of lumbar spondylosis. Two authors assessed trial quality and extracted data from published papers. Additional information was sought from the authors if necessary. Thirty-one published RCTs of all forms of surgical treatment for degenerative lumbar spondylosis were identified. The trials varied in quality: only the more recent trials used appropriate methods of randomization, blinding and independent assessment of outcome. Most of the earlier published results were of technical surgical outcomes with some crude ratings of clinical outcome. More of the recent trials also reported patient-centered outcomes of pain or disability, but there is still very little information on occupational outcomes. There was a particular lack of long term outcomes beyond two to three years. Seven heterogeneous trials on spondylolisthesis, spinal stenosis and nerve compression permitted limited conclusions. Two new trials on the effectiveness of fusion showed conflicting results. One showed that fusion gave better clinical outcomes than conventional physiotherapy, while the other showed that fusion was no better than a modern exercise and rehabilitation programme. Eight trials showed that instrumented fusion produced a higher fusion rate (though that needs to be qualified by the difficulty of assessing fusion in the presence of metal-work), but did not improve clinical outcomes, while there is other evidence that it may be associated with higher complication rates. Three trials with conflicting results did not permit any conclusions about the relative effectiveness of anterior, posterior or circumferential fusion. Preliminary results of two small trials of intra-discal electrotherapy showed conflicting results. Preliminary data from three trials of disc arthroplasty did not permit any firm conclusions. Limited evidence is now available to support some aspects of surgical practice. Surgeons should be encouraged to perform further RCTs in this field.


Effect of glutathione peroxidase activity on lipid peroxidation in biological membranes.
Results are presented indicating that, although glutathione peroxidase activity inhibits lipid peroxidation in membranes, it does not appear to do so by reducing membrane lipid peroxides to lipid alcohols, as has been shown by others to be the case for free fatty acid peroxides in solution. Lipid peroxidation was studied in an enzymic system (microsomal NADPH oxidase) and in a non-enzymic system (mitochondria plus ascorbate). A study of the fatty acids in the phospholipids of microsomes and mitochondria demonstrated that detectable amounts of hydroxy fatty acids were not formed in the membranes when the latter were incubated in the presence of the glutathione peroxidase system even under conditions known to have generated significant levels of lipid peroxides in the membrane. Fatty acid analyses of the microsomal and mitochondrial particles indicated that glutathione peroxidase activity inhibited loss of polyunsaturated fatty acids when these organelles were exposed to peroxidizing conditions. If glutathione peroxidase activity were inhibiting the formation of malondialdehyde (a product of lipid peroxidation) by converting peroxide groups to alcohols, the loss of the constitutive polyunsaturated fatty acids in the membrane should not have been appreciably affected by addition of the peroxidase system. The protective effect cannot be due to quenching of an autocatalytic type of lipid peroxidation (at least in the microsomal system) since it has been established that the microsomal enzyme system (NADPH oxidase) catalyzes a continuous attack on microsomal polyunsaturated fatty acyl groups during the reaction and that the peroxidative process is not autocatalytic in nature. It appears, therefore, that glutathione peroxidase activity must exert its effect on this system by preventing free radical attack on the polyunsaturated membrane lipids in the first place. A possible mechanism for the interruption of a free radical attack on the lipids is proposed.


Search for supersymmetry at the LHC in events with jets and missing transverse energy.
A search for events with jets and missing transverse energy is performed in a data sample of pp collisions collected at √s=7 TeV by the CMS experiment at the LHC. The analyzed data sample corresponds to an integrated luminosity of 1.14 fb(-1). In this search, a kinematic variable α(T) is used as the main discriminator between events with genuine and misreconstructed missing transverse energy. No excess of events over the standard model expectation is found. Exclusion limits in the parameter space of the constrained minimal supersymmetric extension of the standard model are set. In this model, squark masses below 1.1 TeV are excluded at 95% C.L. Gluino masses below 1.1 TeV are also ruled out at 95% C.L. for values of the universal scalar mass parameter below 500 GeV.


Control of anisotropic diffraction in liquid-crystal composite volume gratings.
Orientation-controlled anisotropic diffraction gratings are realized by interferometric exposure using composite materials of nematic liquid crystals (LCs) and LC diacrylate monomers. The anisotropic diffraction properties in volume gratings, which dominantly diffract p- or s-polarized light, are shown to be controlled by the rubbed directions of the alignment layers under the control of the photopolymerization temperature. Images of the fringe patterns observed by polarization microscopy show the effects of the alignment layers on the LC orientation during grating formation.


Physiology of peripheral neurons innervating otolith organs of the squirrel monkey. I. Response to static tilts and to long-duration centrifugal force.
1. The response to static tilts was studied in peripheral otolith neurons in the barbiturate-anesthetized squirrel monkey (Saimiri sciureus). Each unit was characterized by a functional polarization vector, which defines the axis of greatest sensitivity. A circumstantial criterion was used to assign units to the inferior (IN) or superior (SN) vestibular nerves. The former neurons should innervate the sacculus, the latter mainly the utriculus. Confirming pasting experiments, the polarization vectors for SN units lay near the plane of the utricular macula, those for IN units near the plane of the saccular macula. The polarization vectors for IN units were compared in two groups of animals. In one group, the vestibular nerve was intact; in the other, the superior nerve was sectioned. No differences were found and this, together with other observations, demonstrate that the sacculas in mammals functions mainly (if not solely) as an equilibrium organ. 2. The resting discharge of otolith neurons averages some 60 spikes/s, the sensitivity some 30-40 spikes/s-g. IN units tend to have slightly lower sensitivities than do SN units. IN units with upwardly directed (+Z) vectors have substantially higher resting discharges than do units with downwardly directed (-Z) vectors. The +Z units are also characterized by more linear force-response relations. 3. There is a strong positive relation between the resting discharge and sensitivity of units characterized by regular steady-state discharge patterns. A weaker, but statistically significant, relation is demonstrable for irregular units. It is suggested that the relation seen in regular units is the result of the neurons differing from one anothrer in terms of a receptor bias, a transduction gain, or both. Only the mechanism based on transduction gain is thought to be operative among the population of irregular units. 4. Centrifugal-force trapezoids were used to study the response adaptation to prolonged stimulation. Adaptation was more conspicious in irregular units and was characterized by perstimulus response declines and poststimulus secondary responses. For regular units, adaptive properties were similar during excitatory and inhibitory responses. For irregular units, response declines were larger during excitatory stimuli, secondary responses larger following inhibitory stimuli. Typically, response declines were most rapid at the start of the force plateau. A few units, all of them irregular, exhibited a delayed adaptation with response declines beginning only after a constant force had been maintained for 10-20 s. 5. Excitatory responses of regular units are almost always larger than inhibitory responses. This is so during both the dynamic and static portions of force trapezoids. A similar asymmetry is seen in the dynamic response of irregular units; static response asymmetries of the latter units are more variable.


Publishing on policy: trends in public health.
Our goal was to explore the number and topics of policy articles published in general public health journals. We conducted an audit of articles in 16 public health journals from 1998 through 2008. Results showed no trends for the decade studied; only 3.7% of all articles published in these journals were policy-related, and the topics most represented were smoking/tobacco, health care, and school policy. As policy research on public health issues continues to develop, researchers have an opportunity to increase dissemination through publication in general public health journals.


A Bayesian adaptive phase II clinical trial design accounting for spatial variation.
Conventional phase II clinical trials evaluate the treatment effects under the assumption of patient homogeneity. However, due to inter-patient heterogeneity, the effect of a treatment may differ remarkably among subgroups of patients. Besides patient's individual characteristics such as age, gender, and biomarker status, a substantial amount of this heterogeneity could be due to the spatial variation across geographic regions because of unmeasured or unknown spatially varying environmental and social exposures. In this article, we propose a hierarchical Bayesian adaptive design for two-arm randomized phase II clinical trials that accounts for the spatial variation as well as patient's individual characteristics. We treat the treatment efficacy as an ordinal outcome and quantify the desirability of each possible category of the ordinal efficacy using a utility function. A cumulative probit mixed model is used to relate efficacy to patient-specific covariates and geographic region spatial effects. Spatial dependence between regions is induced through the conditional autoregressive priors on the spatial effects. A two-stage design is proposed to adaptively assign patients to desirable treatments according to each patient's spatial information and individual covariates and make treatment recommendations at the end of the trial based on the overall treatment effect. Simulation studies show that our proposed design has good operating characteristics and significantly outperforms an alternative phase II trial design that ignores the spatial variation.


Sensitivity to electricity--temporal changes in Austria.
An increasing number of persons suffer from non-specific health symptoms such as headache, sleep disturbances, difficulties in concentrating and more. In lack of a medical explanation, more and more persons take refuge to the assumption that they were electromagnetic hypersensitive (EHS) and electromagnetic pollution causes their problems. The discussion whether electromagnetic fields (EMF) could cause such adverse health effects is still ongoing. Based on the Austrian inhabitants a statistical cross-sample of the general population with regard to age, gender and federal state had been investigated to assess the actual situation and potential temporal changes in comparison with a former study of 1994. In a telephone survey a total number of 526 persons were included. This study showed an actual EHS prevalence of 3.5% compared with 2% estimated in 1994. About 70% of the sample believed that electromagnetic pollution could be a risk factor for health. More than 30% declared to at least some degree to be concerned about their well-being near mobile phone base stations or power lines. However, only 10% were actively looking for specific information. Media triggered EHS hypothesis in 24% of the cases. The results show that concerns about EMF did not decrease with time in spite of scientific studies and health risk assessments concluding that a causal relationship of EMF below recommended reference levels and non-specific health symptoms would be implausible.


Collective memory, group minds, and the extended mind thesis.
While memory is conceptualized predominantly as an individual capacity in the cognitive and biological sciences, the social sciences have most commonly construed memory as a collective phenomenon. Collective memory has been put to diverse uses, ranging from accounts of nationalism in history and political science to views of ritualization and commemoration in anthropology and sociology. These appeals to collective memory share the idea that memory "goes beyond the individual" but often run together quite different claims in spelling out that idea. This paper reviews a sampling of recent work on collective memory in the light of emerging externalist views within the cognitive sciences, and through some reflection on broader traditions of thought in the biological and social sciences that have appealed to the idea that groups have minds. The paper concludes with some thoughts about the relationship between these kinds of cognitive metaphors in the social sciences and our notion of agency.


Hazelnut (Corylus avellana) vicilin Cor a 11: molecular characterization of a glycoprotein and its allergenic activity.
In Europe, hazelnuts (Corylus avellana) are a frequent cause of food allergies. Several important hazelnut allergens have been previously identified and characterized. Specific N-glycans are known to induce strong IgE responses of uncertain clinical relevance, but so far the allergenic potential of glycoproteins from hazelnut has not been investigated. The aim of the study was the molecular characterization of the glycosylated vicilin Cor a 11 from hazelnut and the analysis of its allergenic activity. Although MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS showed that one of two potential glycosylation sites of Cor a 11 was glycosylated, CD spectroscopy indicated that recombinant and natural Cor a 11 share similar secondary structures. Thus to analyse the impact of the glycan residues of Cor a 11 on IgE binding, the allergenic activity of natural glycosylated Cor a 11 and recombinant Cor a 11 was compared. In addition, the IgE sensitization pattern to recombinant Cor a 11, Cor a 1, Cor a 2 and Cor a 8 of 65 hazelnut allergic patients was determined in vitro. The prevalence of IgE reactivity to hazelnut vicilin Cor a 11 was below 50%. Basophil histamine-release assays were used to determine the allergenic activity of both natural and recombinant Cor a 11 in comparison with Cor a 1, a birch (Betula verrucosa) pollen-related major hazelnut allergen. Both forms of Cor a 11 induced mediator release from basophils to a similar extent, indicating that the hazelnut allergic patients had cross-linking IgE antibodies binding to the protein backbone and not to carbohydrate structures. In comparison to Cor a 1, a 10000-fold higher concentration of Cor a 11 was required to induce similar basophil mediator release. In conclusion, the hazelnut vicilin Cor a 11 is a minor allergen both in regard to prevalence and allergenic potency, whereas its glycan does not contribute to its allergenic activity.


Bis benzothiophene Schiff bases: synthesis and in silico-guided biological activity studies.
Since benzo [ b ] thiophene scaffold is one of the privileged structures in drug discovery as this core exhibitsactivities for different biological problems, in this study bis (benzo[ b ]thiophene-2-yl) alkyl methanimine derivatives (1-9) were synthesized by reacting benzo[ b ]thiophene-2-carbaldehyde with diamines. All newly compounds were characterized by IR, 1H NMR and 13C NMR spectroscopic methods. Synthesized compounds were investigated using binary QSARbased models on therapeutic activity prediction of synthesized compounds and they showed high predicted activities in following diseases: bacterial, angina, allergy, depression and obesity. Thus, they were then tested for their antimicrobial and antileishmanial activities as a result of this theoretical study. Compound 1(N, N'- (propane-1,3-diyl) bis (1-(benzo [ b ] thiophene-2-yl)) methanimine) was found the most active compound in both diseases. Thus, its molecular docking studies were also carried out.


The Effects of Citric Acid Crosslinking on Fabrication and Characterization of Gelatin/Curcumin-Based Electrospun Antioxidant Nanofibers.
Nanofibers, produced through the novel method of electrospinning, have a high ratio of surface area to volume, which allows them to have different optical, electrical, thermal, and mechanical properties than macroscale materials. In this study, it was aimed to produce nanofibers with gelatin and curcumin. The effects of gelatin concentration and crosslinking with citric acid on the characteristics of electrospun nanofibers were studied. Gelatin film containing neither citric acid nor curcumin was used as control. Solutions were evaluated by solution conductivity, color analysis, and rheological properties. Obtained nanofibers were characterized by morphological analysis (SEM), antioxidant activity (AA), thermal properties (TGA, XRD, DSC), water vapor permeability (WVP), and Fourier transform infrared (FTIR) analysis. It was found that the functional groups of gelatin were not changed significantly but some degree of crosslinking was seen, as indicated by the changes in AA, crystallinity, etc. Improvement in antioxidant activities was seen, which was the highest for gelatin and curcumin films (32%). The highest melting temperature (78 °C) and WVP (2.365 × 10-10 gm-1 s-1 Pa-1) was seen for gelatin and curcumin films crosslinked with 0.5% citric acid. Gelatin with curcumin films crosslinked with 1% citric acid showed the lowest crystallinity (1.56%). It was concluded that even though citric acid might not prove to be a stable crosslinking agent for the protein (gelatin), it contributed to the antioxidant nature of the films, along with curcumin. These films are promising candidates to be applied on cut fruits, to reduce water loss and oxidation and hence extend their shelf lives.


Assessment of sesquiterpene lactones isolated from Mikania plants species for their potential efficacy against Trypanosoma cruzi and Leishmania sp.
Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0.7, 0.08 and 2.5 μg/mL, for each compound respectively). These sesquiterpene lactones were also active against the bloodstream trypomastigotes (50% inhibitory concentrations for each compound were 2.1, 1.5 and 0.3 μg/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 μg/mL, respectively). By contrast, scandenolide was not active on Trypanosoma cruzi. Besides, mikanolide and deoxymikanolide were also active on Leishmania braziliensis promastigotes (50% inhibitory concentrations of 5.1 and 11.5 μg/mL, respectively). The four sesquiterpene lactones were tested for their cytotoxicity on THP 1 cells. Deoxymikanolide presented the highest selectivity index for trypomastigotes (SI = 54) and amastigotes (SI = 12.5). In an in vivo model of Trypanosoma cruzi infection, deoxymikanolide was able to decrease the parasitemia and the weight loss associated to the acute phase of the parasite infection. More importantly, while 100% of control mice died by day 22 after receiving a lethal T. cruzi infection, 70% of deoxymikanolide-treated mice survived. We also observed that this compound increased TNF-α and IL-12 production by macrophages, which could contribute to control T. cruzi infection.


Lifetime and actual prevalence of pain and headache in multiple sclerosis.
The aim of the present study is to assess the actual and lifetime frequency of neuropathic (trigeminal neuralgia, L'Hermitte's sign, dysesthesic pain) and somatic (painful muscle spasms and low back pain) pain and headache (tensive headache and migraine) in a cross-sectional sample of 428 consecutive multiple sclerosis (MS) outpatients followed-up in an Italian University MS center over a 3-month period. The impact of demographic and disease-related variables on pain and headache risk is also studied. A semi-structured questionnaire was administered during a face-to-face interview with MS patients and a multivariate logistic regression model is applied to obtain crude and adjusted risk measures. The mean age of the sample was 38.4 years, and female/male ratio was 1.65. The mean disease duration was 9.6 years and the median Expanded Disability Status Scale was 2.0, with most of the patients (74.8%) being affected by the relapsing-remitting form. Lifetime prevalence at the date of examination of at least one type of neuropathic or somatic pain was 39.8% in MS patients, with 58.5% also including headache, while the actual prevalence was 23.8% and 39.9%, respectively. After multivariate analysis, a progressive course of disease was shown to increase the risk of dysesthesic pain and painful muscle spasms, while greater disability was responsible for a higher risk of back pain. L'Hermitte's sign was more frequent in younger patients, while females had a higher risk of headache. Pain and headache in MS are not negligible symptoms and a neurological examination should not miss the assessment of risk factors for specific types of pain for a more specific and individualized treatment.


Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference?
The current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. The implementation of so-called genotyping and phenotyping strategies, and therapeutic drug monitoring, may probably be of more clinical value. In the end, the nonscientifically based BSA-based dosing strategy should be replaced by alternative strategies. Despite the lack of basic fundamentals, BSA-based dosing still seems "untouchable" in clinical oncology. Even when alternatives will be shown to be indisputably better, many hurdles will probably have to be overcome before physicians will be willing to ban BSA-based dosing. Disclosure of potential conflicts of interest is found at the end of this article.


A review on five cases of intramedullary dermoid cyst.
Intramedullary dermoid cyst is a type of rare congenital intraspinal lesions. Its proximity and its strong adherence to the surrounding spinal cord tissue often make a complete resection of the cyst wall problematic. We retrospectively studied five cases of intramedullary dermoid cyst, focusing the recurrence of intramedullary dermoid cyst after surgery and the probable method to prevent the recurrence. Five cases of intramedullary dermoid cyst with or without other concomitant deformities were retrospectively reviewed. Subjects consisted of three males and two females, aged 2–24 years. Diagnosis was confirmed by spinal MRI and pathology studies. Surgical outcomes were analyzed. In case 2, an Ommaya reservoir was implanted in the cystic cavity, and the cystic content was sucked though the Ommaya reservoir. An 18–113 months of follow-up was conducted. The contents of intramedullary dermoid cyst were loose and easy to be cleared in the operations. The cyst wall was closely adhered to the spinal cord, and complete resection was difficult. During the follow-up of 18–113 months, the lesion reoccurred in three cases. Intramedullary dermoid cyst is prone to recurrence. The presence of residual cyst wall might be the cause of dermoid cyst recurrence. When a complete resection of cyst wall becomes infeasible, placement of an intraspinal Ommaya reservoir may help to delay and minimize clinical symptoms by aspiration of cystic contents in case of recurrence.


[Serological markers of Spanish and immigrant pregnant women in the south of Madrid during the period 2007-2010].
The prevalence and evolution of the markers including in the serologic profile of pregnant woman was studied in our hospital during a period of 4 years. A retrospective study of the prevalence of antibodies against Treponema pallidum, human immunodeficiency virus (HIV), Toxoplasma gondii, rubeola virus and hepatitis B virus (HBV), was performed in our hospital among Spanish and immigrant pregnant women, from January 2007 to December 2010. A total of 8,012 pregnant were studied, 2,752 (34.2%) of them were foreign. The non-treponemal tests (RPR) were positive in 40 (0.49%) women, being the prevalence slightly superior in foreigners than in natives (0.8 as opposed to 0.3%). The IgG anti-T. gondii global prevalence was 23,35% (1,874 patients). In Spanish pregnant this prevalence was 18%, and 33.8% in the immigrant women. Almost the total of Spanish pregnant (99.5%) displayed IgG antibodies against rubeola virus whereas in the foreigners this rate was 61.6%. The presence of HBsAg for HBV was tested in 86.6% of pregnant women (6,939/8,012), being positive the 0.75% (59 patients), with a prevalence in foreigners greater than in Spanish (1.65 as opposed to 0.4%). Antibodies anti-HVI were detected in 22 patients (0.22%), being the prevalence 0.15% among the Spanish and 0.51% among the foreigners.